a
Division of Clinical Pharmacology, E240, Sunnybrook and Women's
College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario,
Canadab Department of Pharmacology, University of Toronto,
Toronto, Ontario, Canadac Toxicology Unit, Department of Chemical Pathology,
South African Institute for Medical Research, University of the
Witwatersrand, Witwatersrand, South Africad Gaia Research Institute, Knysna, South Africa

Received
8 February 2001; received in revised from 21 March 2001; accepted
27 March 2001

Objectives:
To review the literature on the toxicity of Callilepis laureola,
and to assess the cytotoxicity of C. laureola in human hepatoblastoma
Hep G2 cells in vitro.

Design and methods: Cells
were incubated for up to 48 h in the presence of increasing concentrations
of an aqueous extract of C. laureola (0.3-13.3 mg/mL). Cytotoxicity
was quantitated spectrophotometrically by the metabolism of the
tetrazolium dye MTT. Cytoviability of the control cells was considered
to be 100%.

There is a mythical yet predominant
view that herbal medicines are harmless and free of side effects
because they are “natural”. There have been several
cases, however, of hepatic injury and even death associated with
their use. The effective and safe use of medicinal herbs has therefore
been identified as a top research priority; and the implementation
of regulatory procedures and investigations on safety are currently
underway in developed countries.

While not
addressed as frequently in the literature, the safety of herbal
medicines used in underdeveloped countries is also a major concern.
In South Africa, it is estimated that between 60 – 85% of
the native population use traditional medicines, usually in combinations.
Cases of acute poisoning due to traditional medicines are not uncommon,
many of which have resulted in significant morbidity and mortality
(18) , with mortality estimated to be as high as 10,000-20,000 per
annum (19).

Venter and Joubert
analyzed cases of acute poisoning admitted to Ga-Rankuwa Hospital,
Pretoria over a 5 year period (1981-1985). Overall, poisoning with
traditional medicines resulted in the highest mortality, accounting
for 51.7% of all deaths that were due to acute poisoning.
Patients were predominantly male and the majority of admissions
were children between the age of 1-5 years. Traditional
healers were the main source of the medicines, and in some cases
substances were bought at a shop for African remedies (21) .
The majority of poisonings were accidental, only 4% were due to
deliberate self-poisoning. A study by Stewart et al. analyzed
the Johannesburg forensic database over 5 years (1991-1995) and
found that (African) traditional remedies were involved in 43% of
poisoning cases (22) .

While these studies
have provided estimates, it is suspected that the true number of
poisoning cases from traditional medicines is far greater (23) .
Medically certified information on the mortality among native South
Africans is lacking, especially for rural areas where deaths are
not always registered (19, 23) . Many poisoning cases are thought
to remain undiagnosed since patients residing in rural areas may
die before reaching a hospital (23) . Furthermore, autopsies are
not routinely conducted, and the cause of death is not always determined
or documented on the certificate, thus many poisoning cases may
go unrecognized.

Detection of traditional
medicine poisoning is further complicated due to the lack of analytical
techniques required to make a confident diagnosis. Due
to a shortage in resources, diagnostic tools are either limited
or have not yet been developed. Moreover, the plant component of
the traditional remedy responsible for the observed toxicity may
not be known. In some cases, the culprit plant has been identified
through direct questioning. People are generally very reluctant
to admit the use of herbal remedies, however, often because hospitals
tend to hold a negative view toward traditional medicines, and
also because of the cultural secrecy surrounding their use.

In the present study,
we investigate the in vitro hepatotoxicity of one known
toxic herb: Callilepis laureola. C .laureola is
a traditional remedy commonly used by the Zulu who are predominantly
located in the KwaZulu-Natal region in the northeast of South Africa.
C. laureola, a member of the family Compositae, is a herbaceous
perennial plant found commonly in grassland habitats of eastern
South Africa. C. laureola is known to be “very poisonous and
has even been responsible for several deaths among the Zulu”.
It has been estimated that the plant is responsible for up to 1500
deaths per annum in KwaZulu-Natal alone, one of nine provinces
in South Africa (27, 32) . The plant is commonly known as
Impila, which ironically is the Zulu word for “health”.

Although there are
no approved medical uses of Impila from a health regulatory standpoint,
the plant is widely used among the Zulu and appears to serve as
a multi-purpose remedy (22) . Reports indicate it is used
to treat stomach problems, tape worm infestations, impotence, cough,
and to induce fertility. Impila is also administered to pregnant
women by traditional birth attendants to “ensure the health
of the mother and child” and to facilitate labour. A tonic
made from the root is also taken by young girls in the early stages
of menstruation. The greatest and most valued attribute of this
plant, however, appears to lie in its “protective powers”
in warding off “evil spirits”. For example parents who
have lost previous children to illness may administer Impila enemas
to their current children for the belief it will “protect”
them. It is suspected that these magical beliefs are the
primary reason for the common use of Impila in young children,
and the high Impila-related mortality in children under the age
of 5 years (22) .

Impila is most
often prepared using the tuberous rootstock of the plant, while
the leaves are reputed to have minimal curative properties. The
tuber may be harvested and collected in the winter, and dried and
crushed into a powder. Alternatively, a fresh piece of the tuber,
the size of a forefinger, may be chopped and bruised. The resultant
powder is boiled for approximately 30 minutes to 1 hour in a suitable
volume of water and the decoction is administered either orally
or as an enema. It has been estimated that each dose of the herbal
remedy is prepared from approximately 10 grams of plant material
(32) .

The danger of C. laureola
was first documented in 1909. Numerous cases of Impila-induced
hepatic and renal toxicity emerged in the medical literature during
the 1970s and since this time there have been regular reports of
fatal Impila intoxications. The toxicity of Impila
appears to be very sudden in onset, and it is suspected that many
patients do not reach a hospital before death (22) . The
fatalities due to C. laureola toxicity are significant. As reported
by various investigators, it is estimated that 63% of patients die
within 24 hours, and a further 28% die within 5 days, thus bringing
the total mortality to 91% (23).

Despite it’s
reputed toxicity, Impila continues to be a very popular
and commonly used traditional remedy in South Africa (23) . If the
toxicity of C. laureola is so well established, why then
is the plant still being used significantly in South Africa? There
appears to be several complex answers to this question. Currently
there is no legislation controlling traditional medicines in South
Africa, and the regulatory standards and public education required
to ensure their safe use have yet to be implemented (19) . In rural
areas, traditional healers are the primary source for obtaining
such medicines, whereas in towns and cities, traditional medicines
are readily available in African medicine shops where they are sold
over-the-counter.

Another issue to consider
is the cultural context in which traditional medicines are used.
Impila is most commonly used for the magical properties
it is believed to possess. While some illnesses are attributed to
natural causes, others are thought to be the result of an “evil
spell”, or the consequence one must suffer for violating the
ancestral spirits. The respect for traditional healers and the belief
in the curative properties of traditional medicines is so deep-rooted,
that often a fatality resulting from a toxic herb will wrongfully
be blamed on the underlying “illness” for which the
herb was taken. Other points of consideration are the factors that
affect the toxicity of the herb itself. The toxicity of some plants
is known to vary with season.

The lack of safety regulation
and the ease at which herbal medicines may be obtained likely increase
the occurrence of fatal errors among traditional healers, vendors
and the public in regards to the strict “ancient rules”
regarding the use of Impila as an herbal remedy: “impila
is never given to a child under the age of 10; it is never given
by way of an enema; it is never used in arbitrary doses nor in any
but the weakest solution; when swallowed, it must never be allowed
to be absorbed; in other words, it is used exclusively in the form
of treatment known as phalaza (i.e. swallowing a large
volume of a weak decoction, followed by immediate inducement of
complete or near-complete catharsis). There is little doubt that
a lack in knowledge and awareness of these strict rules has contributed
to the numerous cases of Impila-induced fatalities.

Although clinical cases
of C. laureola-induced toxicity are well documented in the literature,
the mechanism by which the plant produces hepatic and renal toxicity
is not completely understood. Cases of human poisoning with C. laureola
have been researched by various investigators in South Africa and
are well documented in the literature. Diagnostic methods to confirm
such poisonings are in the process of development (22) . The mechanism
by which C. laureola produces hepatotoxicity is still not known,
and to date there are no published data available on the plant’s
effects in vitro. Therefore, as a starting point, we report preliminary
results of the hepatotoxic effects of C. laureola in vitro using
the human hepatoblastoma Hep G2 cell line.

Our results suggest that
the principle target of C. laureola-induced toxicity is
the mitochondria. The mechanism appears to involve a metabolite-induced
opening of the mitochondrial permeability transition pore (MPTP),
release of cytochrome c, and caspase activation. Whether apoptosis
or necrosis is the predominant mode of cell death involved in C.
laureola intoxication will have clinically important implications
for treatment interventions and the development of antidotes. The
in vitro model used in the present study will be a useful
tool to study the mechanism of C. laureola-induced hepatocyte death,
and further investigations in this direction are currently in progress.

(For the full technical
aspects of this paper, see the full text PDF version associated
with this introductory extract.)

In
2001 my Canadian colleagues (Popat et al) and I (Stuart Thomson,
South Africa) published a collaborative paper in the respected
journal, Clinical Biochemistry, dealing with the toxicology
of traditional African medicine from the southern African
plant Callilepsis laureola, commonly known as Impila. Conservative
forces in South Africa, attempted to have our paper withdrawn,
complaining that my Report to the Medicines Control Council
had not been peer-reviewed. It is not unusual to cite such
sources, but said forces, being partly responsible for public
safety from such medicines, were clearly embarrassed that
my realistic conservative estimate of 10,000-20,000 annual
deaths from traditional African medicines in South Africa
had been recorded in the international medical literature.
Our two published papers and a published letter exchange are
linked below in their original format as downloadable pdf
files.

My letter to the Editor,
immediately hereunder, was withdrawn in favour of a group
letter, since the Publisher would only publish one letter
from our group. I am however posting my letter here, since
it not only clearly illustrates the strength of my extrapolations,
but more importantly, ends (Comments on Du Plooy and Robson's
changing pattern in deaths) with an exposé of the errors,
if not downright fraudulent nature, of my opponent’s
position.

The Editor
Clinical Biochemistry

6 February
2001

Dear Sir

Response
to du Plooy and Jobson: Estimated Mortalities Due To Traditional
African Medicines In South Africa

I humbly submit the following for your
urgent consideration for publication in the letters pages of Clinical
Biochemistry.

The estimate of 10-20,000
deaths p.a. from traditional African medicines (TAM) in South Africa,
cited in "Popat A, et al, Clin Biochem, 34, 2001" as "Thomson
S, Traditional African Medicine Genocide and Ethnopiracy, Report
to the SA Medicines Control Council, Gaia Research Institute, March
13, 2000" has been criticized without substitution by du Plooy
and Jobson as conjecture and lacking peer review. Following requests
from the Centre for Epidemiological Research and Trauma Research
Unit, both at the SA Medical Research Council, a response was prepared
for a review of my methodology, presented below in abbreviated and
adapted form for consideration by Clinical Biochemistry readers
and detractors. In spite of repeated requests for critique or attempted
rebuttal, none has been forthcoming in the subsequent 23 months.
If space permits, I have critiqued the mentioned du Plooy et al
paper, so that readers might witness and understand their apparent
desperation and mischievous intent.

Data on mortality in South
Africa is inadequate. The absence of a comprehensive national health
information system poses problems for analysis. (White
Paper on Population Policy, RSA, March 1998) The SA
MRC conceded the dilemma a year prior, stating: “Estimating
specific causes of death in South Africa is difficult, the last
detailed information being almost a decade old, since the law was
changed at that time to exclude the necessity of recording the details
of the actual cause of death. The data collection system makes no
provision for gathering the type of data needed to determine how
many deaths might be attributable to traditional medicines. The
overall figures must all be considered to be vast underestimates.
There are major problems with the data. Not all deaths in rural
areas are registered and many are in the ill-defined category where
it was not specified on the certificate.” (Pers
comm, Dr D Bradshaw, Centre for Epidemiological Research in Southern
Africa, MRC, 6 April 1999)

The data used is the only
available, namely, "Bradshaw D, Health and Related Indicators,
SA Health Review, 1997", and "Recorded Deaths, 1994, CSS
Report No. 03-09-01, Central Statistical Services, Pretoria, 1994".
Figures used for comparison were those of the Dept of Health (DoH),
confirming the validity thereof. My reasoning is elementary, as
follows: The crude death rate in South Africa is 8.9 per 1000 (RSA
Stats in Brief, Aug 1996), (9.4/1000 according to DoH), so approximately
400,000 of 40 million die each year. In SA 19.56% of all deaths
are of unnatural causes (20% DoH), excluding homicide, violence,
accidents and self-afflicted. (Bradshaw
D, Estimated Cause of Death Profiles SA, Based on 1990 Data, CERSA,
MRC, 1991) 20% of 400,000 clearly suggests 80,000 deaths
from unknown causes p.a., possibly from TAM.

Amongst black South Africans,
poisoning is the second in order of importance in the five main
causes of death. (Van Rensburg H & Mans A, Profiles of Disease
and Health Care in South Africa, R&H Academica, 1982) The major
cause of fatal poisoning pattern reported at Ga-Rankuwa is very
similar to Bloemfontein (and Zimbabwe). The major causes of mortality
were TAM, responsible for 51.7 % - 62% of deaths. (Joubert
P, J Toxicol Clin Toxicol 28(1), 1990) Many cases are
undiagnosed, where patients die without reaching hospital and do
not often admit to ingestion of a traditional remedy. (Steenkamp
V, et al, Hum Exp Toxicol 18(10), 1999)

It is not unrealistic to
assume that TAM is responsible for 10-20% of the deaths from unknown
causes, ie 8-16,000. Assuming that just 12,000 (3%) of the deaths
from natural causes are likely to be incorrectly allocated TAM mortalities,
simply because it is not possible to determine the true causes in
all cases and because the symptoms and causes from traditional medicines
closely mirror the major causes of death among the South African
black population (diarrhoea, fetal distress and renal, hepatic,
respiratory & cardiac failure), 20-30,000 would be a realistic
estimate, yet I settle for a far more conservative (1.5%) estimate
of 10-20,000 TAM mortalities p.a..

In concurrence, US computerized
data for nosocomial adverse drug reaction mortalities exceed 100,000
annually. (Lazarou B, et al, Incidence
of Adverse drug reactions in hospitalized patients: A meta-analysis
of prospective studies. JAMA, 279: 1200-5, 1998) In
South Africa, allopathics are in a 20% minority to 80% for traditionals.
A simple extrapolation based on the (1990) US population of 260
million compared to SA’s 40 million, suggests 15,000 ADR mortalities
for SA. However, the US figures reflect actual captured data, the
true figure being estimated to be double that, in real terms. (Holland
E & Degruy F, Amer Home Physician, 56(7), 1997) In SA, 15-30,000
likely ADR mortalities are therefore distributed between allopathic
and traditional drugs, supporting my original TAM mortality estimate
of 10-20,000 as fairly conservative.

The US figures are for scientific
medical drug related hospital deaths, yet ADR’s still rank
from the 4th to 6th leading cause of death.
(Editorial, Bandolier, UK NHS, June, 52-3, 1998); (White T, et al,
Pharmacoeconomics, 15(5), 1999) Contrast this with the
Third World facilities and drugs that most African patients do not
consider capable of addressing the supernatural causes of their
illness/misfortune, let alone avail themselves to. Furthermore,
the 400,000 traditional healers and vendors serving 80% of the population
do not prescribe or supply TAM on any rational basis other than
superstition and their ability to engage patients as drugs of ordeal,
to appease angry ancestors rather than for any pharmacological action.
Given these circumstances, it is unlikely that South Africa would
escape this extrapolated ADR mortality burden.

Comments on Du Plooy and Robson's changing pattern in deaths due
to traditional medicine poisonings in the last twenty years at Ga-Rankuwa
Hospital

In an article cited in a recent letter to the Editor, Clin Biochem,
du Plooy and Jobson state: "In this article we place Joubert's
figure of 51.7% in the correct perspective and provide details of
the extent of mortality due to traditional medicine poisonings in
Ga-Rankuwa patients from July 1996 to July 2000", yet curiously,
they fail to do so. They further state: "Unfortunately we were
unable to obtain the total number of all deaths for the same period
(Mar 97-Mar 98)" and that: "Results are expressed as actual
numbers and percentages in terms of five categories in table",
yet again, curiously they are not, the period is missing from the
table. They do throw around a few figures, including some (only
some) missing from the table, divided into the total number of patients,
but now curiously, inconsistently inflated by those "seen"
or admitted, thereby attempting to trivialise the number of deaths
from TAM, but during a period for which they conveniently have no
total number of deaths. Additionally, unidentified poisonings, which
are likely to include many TAMs, are conveniently excluded from
analysis without any quantification, further placing their results
in question. The du Plooy et al data is incomplete and unsuitable
for comparative analysis. It is alarming that this was peer reviewed
and yet still published in the SA J Sci.

Finally, a serious error
or fraud is committed, whereby they state that: "It is worth
noting that paraffin ingestion "remains" the cause of
the highest number of deaths from poisoning". Again, curiously
the deaths from paraffin are not even shown. Again, utter nonsense.
Paraffin is the biggest cause of acute "poisoning", not
of deaths, which latter have always been and remains due to TAM.
(Venter C, Joubert P, Biomed Environ Sci 1(4) 1988); (Joubert J,
J Toxicol, 28(1), 1990);(Ellenhorn's
Medical Toxicology, M Ellenhorn, Ed, William & Wilkins, 1997)
It is clear to me that du Plooy and Jobson are desperate
to prove something in service of a mischievous agenda.

Sincerely

Stuart Thomson
Director, Gaia Research Institute

DOWNLOADABLE
REPORTS:

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Full Published Impila Report

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Second Published Impila Report

Download
Impila Controversy (Published Letters To The Editor)

Investigations
in the Hepatocytotoxicity of Callilepis laureola (Impila)
a South African Traditional Medicine
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